This work is part of a long-term strategy to define the alterations leading to the immunologic abnormalities of the alcoholic. In addition to the widely reported clinical immune deficiency and disorders with possible autoimmune origins, we and others have demonstrated that chronic alcoholics have (a) persistently activated T lymphocytes, (b) lymphocyte fine subset losses in B cells, T cells, and NK cells, (c) monocyte activation, and (d) a range of functional changes in vivo and in vitro. We now propose five interactive projects (IRPG) to evaluate chronic ethanol effects on innate and adaptive immune system components and the interactions of both with infectious disease agents. In brief, the projects are: (1) T cell dependent immune responses and ethanol; (2) Effect of ethanol on the murine B cell compartment; (3) Dendritic cell function and ethanol; (4) Natural killer cells and ethanol; (5) The role of immune responses in alcoholic liver disease. A key feature of all projects is the use of a model of chronic ethanol administration which we have shown to be well tolerated by mice, can be administered for prolonged periods of time proportional to that seen in humans, and importantly, produces changes similar in many immunologic parameters to changes observed in chronic human alcoholics. This project, (1) T-cell dependent immune responses and ethanol, will investigate T cell dependent alterations by chronic ethanol exposure. We have shown elsewhere that chronic ethanol mice have activated T cells. The literature clearly shows that alcoholics have diminished T dependent immunity, and we have found in preliminary data that mice exposed to chronic ethanol have both decreased antigen-specific T cell responses to Listeria monocytogenes LLO antigen, and altered T dependent humoral response to TNP-KLH. We now propose to evaluate both CD4+ and CD8+ T cell antigen-specific responses to Listeria antigens after prolonged ethanol ingestion, the effect of boosting immunizations and withdrawal on these ethanol-diminished responses, and several experimental protocols to evaluate memory cell survival in chronic ethanol exposure. In other experiments, the effect of chronic ethanol on TH1 and TH2-driven humoral responses will be measured, in both TH1- and TH2-dominant mice. Experiments to distinguish clearly whether T cells from chronic ethanol mice have diminished capacity to respond to normal peptide-loaded bone marrow dendritic cells will be carried out both in vitro and in vivo. DNA vaccines encoding the Listeria LLO protein will be used to attempt to boost ethanol-diminished antigen-specific T cell responses, and to increase both memory cells and antigen-specific cytolytic T cell responses, which are important in protection. ? ?
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